期刊
MOLECULAR NEUROBIOLOGY
卷 59, 期 2, 页码 1214-1229出版社
SPRINGER
DOI: 10.1007/s12035-021-02682-6
关键词
Lafora disease; Malin; p62; Glycogen; Lafora bodies; Neuroinflammation; Epilepsy
资金
- CRUE-CSIC agreement
- Springer Nature
- Spanish Ministry of Science, Innovation, and Universities (MCIU/FEDER/AEI) [BFU2017-84345-P, PID2020-118699 GB-I00]
- CIBER de Diabetes y Enfermedades Metabolicas Asociadas (ISCIII, Ministerio de Ciencia e Innovacion)
- National Institutes of Health [NIH NINDS P01NS097197]
- MCIU/FEDER/AEI [RTI2018-099773-B-I00]
- CERCA Program
- Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya [SGR2017-648]
- MINECO (Government of Spain)
- Severo Ochoa Program at IBEC
- European Union [75451]
Lafora disease (LD) is a fatal childhood-onset dementia characterized by the accumulation of glycogen aggregates in various organs, particularly in the brain. The presence of p62, an autophagy adaptor, plays a role in the formation of these aggregates, suggesting a protective mechanism to mitigate the harmful consequences of glycogen accumulation in the brain.
Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates-the so-called Lafora Bodies (LBs)-in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malin(KO)) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.
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